The main aim of this work is the study of genetically controlled host defense mechanisms involved in protective immunity and recovery from Friend retrovirus complex (FV)-induced erythroleukemia in mice as a model for human retrovirus diseases such as AIDS and leukemia. We have continued previous studies of the influences of H-2 genotype on both FV-induced immunosuppression and protective immunity against FV. Initial results suggested that mice with a high susceptibility to retrovirus induced immunosuppression could not be protected by immunization with a vaccinia recombinant expressing the FV envelope gene product. However, use of H-2 recombinant mice indicated that protective immunity was influenced by the H-2K and I-A subregions, whereas immunosuppression was influenced by the H-2D subregion. Thus, protective immunity was induced even in mice with high susceptibility to FV-induced immunosuppression. These results suggest that humans who are genetically more susceptible to the immunosuppressive effects of HIV infection might still be protected from AIDS with appropriate vaccines. More recent studies on the mechanism of protection in this system indicate that vaccination induces FV-specific T lymphocyte priming. Subsequent exposure by challenge with FV induces cytotoxic T lymphocytes and a secondary humoral antiviral antibody response, both of which may be involved in recovery from disease.